Mononuclear phagocytes have important functions in the host's defenses against environmental injury. Mononuclear phagocytes recognize and destroy neoplastic cells in vitro, when the macrophages are "activated." Macrophages also secrete a wide variety of molecules which alter the extracellular environment and the behavior of other cells. However, the metabolic basis of activation, the way in which activated macrophages destroy neoplastic cells, and the fundamental mechanisms regulating either activation or secretion are ill-defined. We have experimental data that suggest that the nonspecific cytotoxicity of activated macrophages and the secretion of neutral proteases by macrophages are linked and, further, that both functions share common regulatory mechanisms which may involve stimulus-secretion coupling. We therefore propose to: a) Determine the specific relationship between macrophage-mediated cytotoxicity and the secretion of neutral proteases; b) Determine if macrophages secrete a soluble cytotoxin and, if so, determine its character and relationship to neutral proteases; c) Delineate the mechanisms regulating secretion of neutral proteases including the roles of cyclic nucleotides, divalent cations, and serine esterases; and d) Delineate the factors regulating the activation and cytotoxic expression of activated macrophages. The ultimate goals of these studies are to understand how the secretory and cytotoxic functions of macrophages are regulated and related and to apply this knowledge to models of chronic inflammation and tumor destruction in vivo.